Brain-derived neurotrophic factor (BDNF) plays a fundamental role in determining the plasticity and functional architecture of neurons in the adult brain. A frequent, non-conservative polymorphism in the human BDNF gene has been recently identified, which results in impaired secretion of BDNF and may be one factor that increases the susceptibility of an individual to psychiatric disorders brought about by stress, such as major depression. Mice offer a unique opportunity to examine interactions between environmental factors, such as stress, and genetic factors, such as a deficiency in BDNF, in determining behavior. We have interesting preliminary data that indicate that the mild stress of handing and injection of saline, which does not alter behavior in wild-type mice, produces depression-like behavior in male BDNF() mice. Our overall hypothesis is that BDNF deficient mice are more vulnerable to the effects of mild stress than the wild-type mice. We will use intraperitoneal injection of saline as a mild handling stress. The injection of saline will be used as a temporally discrete and simple stressor to which mice easily habituate. Because BDNF promotes activity- dependent synaptic plasticity, and may have a role in the modulation of responses to repeated stress, we hypothesize that mice deficient in BDNF will not habituate to repeated injections of saline. We will measure plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone as a physiological indication of the reactivity of BDNF() mice to stress immediately following the acute (3 injections of saline over 24 hours) and chronic (once daily injection of saline for 7 days) handling stress procedures (Specific Aim 1). In this exploratory application, rather than attempt to model the complex syndrome of major depression, we will model symptoms of depression that are hallmarks of this disorder such as (a) despair, and (b) loss of interest in normally pleasurable activities or anhedonia. To this end, we will measure in BDNF() mice immobility in the forced swim test (Specific Aim 2) and sucrose consumption in a two bottle choice test (Specific Aim 3). We also hypothesize that signs of behavioral depression will be reversed by the tricyclic antidepressant desipramine. Because estrogen positively modulates BDNF mRNA and protein within the hippocampus and cortex, which may make female mice less vulnerability to the deleterious effects of stress, we will conduct these proposed exploratory experiments in both male and female mice. BDNF() mice appear to exhibit characteristics consistent with theoretical or proposed etiology of major depressive disorder. In this exploratory application we further examine the validity of this model by determining the effect of mild handling stress on often used indices of behavioral depression. The validity of this model will make it of great interest to further examine in BDNF() mice the neurobiological and neurochemical mechanisms by which BDNF deficiency confers vulnerability to stress. PUBLIC HEALTH RELEVANCE: Brain-derived neurotrophic factor (BDNF) expression in the brain is decreased by stress and increased by chronic antidepressant treatments. A frequent, non-conservative polymorphism in the human BDNF gene has been recently identified, which results in impaired secretion of BDNF and may be one factor that increases the susceptibility of an individual to psychiatric disorders brought about by stress. Thus, stress-related psychiatric disorders, such as major depression, may result from a subtle atrophy or diminished function of BDNF- responsive neurons in the brain.